CR2 (CD21) is a cellular receptor on B lymphocytes that is implicated in their growth regulation and is linked to intercellular pathways involved in signaling B cell proliferation. Melchers et al., Nature, 317:264 (1985); Lernhardt et al., Immunol. Rev., 99:239 (1987); Bohnsack et al., J. Immunol., 141:2569 (1988); Cooper et al., Ann. Rev. Immunol., 6:85 (1988); Tedder et al., J. Clin. Immunol., 6:65 (1986); Hatzfeld et al., J. Immunol., 140:170 (1988); Frade et al., Proc. Natl. Acad. Sci. USA, 82:1490 (1985).
CR2 occurs on normal B lymphocytes and on B cell neoplasms. Cooper et al., Ann. Rev. Immunol., 6:85 (1988); Hatzfeld et al., J. Immunol., 140:170 (1988). CR2 functions as a receptor for several complement C3 activation products. The proteolytic C3 activation products iC3b, C3dg and C3d all bind to CR2 and have been shown to mediate both stimulating and inhibiting effects on lymphocytes. Weigle et al., in Complement, Muller-Eberhard, H. J. and Miescher, P. A. (eds.), p. 323, Springer-Verlag, Berlin (1985). Because of its central role in B cell function, CR2 function and ligands that modulate that function are of great interest.
The CR2 receptor is also of clinical interest because it is the receptor for the human herpes virus, Epstein-Barr virus. Fingeroth et al., Proc. Natl. Acad. Sci. USA, 86:242 (1989). EBV is the causative agent of infectious mononucleosis, [Henle et al., Proc. Natl. Acad. Sci. USA, 59:94 (1968)] and is possibly a human cancer virus, because it has been linked to nasopharyngeal carcinoma and Burkitt's lymphoma. Henle et al., Science, 157:1064 (1967). In addition, EBV is thought to be associated with x-linked lymphoproliferative disease (Duncan's disease) [Purtillo et al., Lancet i, 935, (1975)] and several human autoimmune disorders. Tosato et al., Adv. Immunol., 37:99 (1985). Lastly, EBV may play a role in the onset of B cell neoplasia observed in a substantial number of patients with AIDS (Yarchoan et al., J. Clin. Invest., 78:439 (1986). In vitro infectious EBV is a T cell-independent B cell stimulator and transforms human B lymphocytes to immortal polyclonal lymphoblastoid cell lines. Cooper et al., Ann. Rev. Immunol., 6:85 ( 1988). Non-transforming virus is a T cell-dependent B cell activator. Cooper et al., Ann. Rev. Immunol., 6:85 (1988). Drug inhibitors of EBV propagation that operate by interfering with virus binding to CR2 will therefore be of clinical relevance.
Some ligands that bind CR2 have been extensively characterized. For example, the exact sequence motif mediating binding of C3 fragments to CR2 has been elucidated by Lambris et al., Proc. Natl. Acad. Sci. USA, 82:4235 (1985) and has the amino acid residue sequence LYNVEA. Peptides containing this motif have the ability to inhibit aggregated C3d-induced S phase entry of B cells [Lernhardt, et al., Immunol. Rev., 9:239 (1987)] and to inhibit alpha B cell growth factor activity. Melchers, et al., Proc. Natl. Acad. Sci. USA, 82:7681 (1985). However, the precise function of a ligand containing this motif is unclear. Monomeric C3b and C3d are inhibitory, whereas aggregated C3b and C3d stimulate B cell proliferation. Erdei, et al., Eur. J. Immunol., 15:184 (1985); Bohnsack et al., J. Immunol., 141:2569 (1988).
The sequence motif mediating binding of EBV virus to CR2 is present on the gp350/220 protein and has the amino acid residue sequence EDPGFFNVE. Nemerow, et al., Cell, 56:369 (1989).
Although the above reports describe CR ligands and CR2 binding motifs, it is not generally understood that species of interferon also contain unique CR2 binding motifs.